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Amino acid utilization was evaluated in seven children with acute lymphocytic leukemia treated with succinylated Acinetobacter glutaminase-asparaginase. All patients received food p.o. ad libitum and glucose-electrolyte solutions i.v.; four patients received an i.v. amino acid supplement (1.5 g/kg/day). Although all patients were in negative energy balance, there was a significant linear regression between nitrogen balance and nitrogen intake during Days 1 to 7 and Days 8 to 14 of the study. The slope of the regression line, reflecting exogenous nitrogen utilization, was not significantly different from that found in healthy young men ingesting adequate or subadequate energy intakes. The Y-intercept (-210 mg/kg/day) indicated an obligatory nitrogen loss that was much greater than normal. Most of the nitrogen loss was due to urinary excretion. Ammonia and urea accounted for 77 to 91% of the urine nitrogen. Urinary glutamate accounted for 4 to 10% of this loss. Urine protein excretion was abnormally high in each of the patients, ranging from 987 to 3440 mg/day. Urine excretion of N-acetyl-beta-glucosaminidase and beta 2-microglobulin was also abnormally high, despite normal blood urea nitrogen and serum creatinine, suggesting that these children had renal tubular dysfunction. The antileukemic effect of succinylated Acinetobacter glutaminase-asparaginase did not appear to be altered by amino acid supplementation. These data indicate that amino acid supplementation can improve nutritional status in patients treated with succinylated Acinetobacter glutaminase-asparaginase.

The effects of Acinetobacter glutaminase-asparaginase (AGA) on protein and energy requirements were evaluated in mice bearing Ehrlich ascites tumors. In an initial experiment with normal mice, a zero protein diet resulted in a significant decrease in carcass nitrogen, liver nitrogen, and carcass energy relative to the animals on a normal, low, or high protein diet. In a second experiment, mice bearing Ehrlich ascites tumors were randomized into diet groups (zero or normal protein) and treatment groups (daily injections of AGA or 0.9% NaCl solution). In both treatment groups, the zero protein diet resulted in significant decreases in weight, liver nitrogen, carcass nitrogen, and carcass energy. Neither tumor nor AGA treatment affected body composition or the efficiency of nitrogen utilization. By Day 8, either the zero protein diet or AGA treatment significantly reduced ascites volume and tumor nitrogen content relative to controls. In a modification of Experiment 2, AGA treatment was stopped on Day 8, and all animals were given a normal protein diet. AGA, but not the zero protein diet, significantly enhanced ultimate survival. These experiments indicate that the requirements and utilization of energy and nitrogen are normal in mice with Ehrlich ascites tumor whether or not they are treated with AGA.

Using a single dose, [15N]glycine turnover technique, whole body rates of proteins synthesis and breakdown were assessed in six healthy children and in eight children with newly diagnosed leukemia (DeWys, W. D. Cancer Res., 42: 721s-726s, 1982) or lymphoma (Baracos, V., Rodemann, H. P., Dinarello, C. A., and Goldberg, A. L. N. Engl. J. Med., 308: 553-558, 1983). Based on excretion of 15N as urinary ammonia, synthesis (g protein per kg body weight per day) was significantly (p less than 0.025) higher in the cancer patients [5.4 +/- 1.5 (S.D.)] compared to the controls (3.6 +/- 0.9); breakdown was also higher (p less than 0.02) in the patients (5.5 +/- 1.8) compared to the controls (3.1 +/- 1.1). When only the seven patients with leukemia were considered, there also were significant increases in synthesis (5.4 +/- 1.6, p less than 0.05) and breakdown (5.4 +/- 1.9, p less than 0.025) compared to controls. Increases in both synthesis and breakdown were also observed in the patients when the protein turnover data were expressed as a function of the rate of creatinine excretion or the calculated lean body mass. We conclude that whole body protein turnover is increased in sick children at the time of diagnosis with some forms of newly diagnosed cancer.

Forty-eight tumor-free mice and 32 mice bearing Ehrlich ascites tumor were randomized into 2 treatments, Acinetobacter glutaminase-asparaginase (AGA) (600 IU/kg/day for 7 days) and 0.9% NaCl controls, and into 2 or 3 isocaloric diets, normal protein (NP) (20 g protein/100 g diet), high protein (HP) (58 g protein/100 g diet), and zero protein (ZP) (tumor-free mice only). In tumor-free, NP-fed mice, AGA caused percentage reductions (P less than 0.01) in the nitrogen content of liver (50%), intestine (42%), thymus (89%), spleen (75%), and carcass (20%), but HP prevented this effect on intestine and carcass and caused percentage increases in the nitrogen content of liver (53%), intestine (36%), thymus (122%), and carcass (25%). In Ehrlich ascites tumor mice (NP or HP fed) AGA caused markedly lower (P less than 0.01) tumor burdens and increased nitrogen content of intestine (HP), kidney (NP and HP), and spleen (NP and HP). Ehrlich ascites tumor, AGA-treated, HP-fed mice ate 31% less food (P less than 0.01) (compared to NP) but HP resulted in percentage increases in the nitrogen content of liver (18%; P = 0.05), intestine (25%; P less than 0.05), and thymus (164%; P less than 0.01). In the Ehrlich ascites tumor, AGA group the HP diet caused higher hematocrit and serum total protein (both, P less than 0.05). Adverse nutritional effects of AGA seen in normal mice were markedly diminished in tumor-bearing animals. The observed nitrogen-sparing effects of the high protein: energy ratio may be relevant to humans and to other forms of neoplasia and chemotherapy.